The powerful rewarding (reinforcing) properties of abused drugs undoubtedly play a major role in substance abuse behavior. Several lines of evidence suggest that the indirect stimulation of nucleus accumbens (NAc) dopamine (DA) receptors by drugs of abuse (particularly cocaine) is a critical event in the neural processes responsible for these rewarding properties. The proposed experiments will utilize techniques in molecular biology to examine NAc DA receptors and the neurons that contain these receptors. Two cDNA clones encoding molecular subtypes of the D2 DA receptor have been isolated (through cDNA hybridization screening or polymerase chain reaction amplification) which may encode novel DA receptor subtypes. Aim #1 will entail isolation, expression, and characterization of corresponding full- length clones to determine whether they encode novel DA receptors. The D2 receptor clones, as well as any novel DA receptor clones, will be used in in situ hybridization histochemistry studies (Aim #2) to determine the cellular distribution of each receptor subtype in the NAc. For each DA receptor subtype, neurotransmitter systems will be identified (with double- labelling techniques) in the NAc neurons containing that subtype. Aim #3 will involve double-labelling protocols combining retrograde tracer injections and in situ hybridization histochemistry to identify the projection fields of NAc neurons containing each DA receptor subtype. Finally (Aim #4), the above mentioned double-labelling techniques, as well as northern analyses, will be used to study the effects of cocaine administration on DA receptor mRNA concentrations and neurotransmitter utilization in anatomically defined subpopulations of NAc neurons.